Protoberberines constitute a family of naturally occurring benzoquinolizinium alkaloids found in plants such as, for instance, Anonaceae, Berbiridaceae, Papaveraceae, Ranunculaceae. Relevant examples of protoberberines are Berberine or 9,10-dimethoxy-5,6-dihydrobenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium; Berberrubine (or Berbine) or 9-hydroxy-10-methoxy-5,6-dihydrobenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium; and Palmatine or 2,3,9,10-tetramethoxy-5,6-dihydrodibenzo[a,g]quinolizinium. The inventive benzoquinolizinium salt derivatives may be also considered and commonly termed as protoberberine derivatives. Both the scientific, IUPAC-recommended and the trivial, common nomenclatures will be used throughout the present specification interchangeably.
U.S. Pat. No. 3,910,938 and U.S. Pat. No. 3,920,665 disclose berbine compounds carrying alkyl, allyl or alkoxy substituents in position 13 as inhibitors of the growth of transplanted sarcoma strains in mice. There is no mention about additional (hetero)aromatic moieties linked to the substituents in position 13.
U.S. Pat. No. 6,008,356 and U.S. Pat. No. 6,030,978 disclose protoberberine derivatives substituted in position 13 by phenylmethyl (benzyl) and pyridylmethyl groups as antifungal agents, and pharmaceutical compositions containing them. Said patent specifications are completely silent in mentioning anything about an anticancer activity, and there is no reference about 13-(di)arylalkyl substituted compounds, even no disclosure or mention about phenylalkyl and pyridylalkyl substituents. Example 1 (13-benzyl) of said US patents was comparatively tested with the novel compounds of our specification, resulting in a much lower antitumour activity.
U.S. Pat. No. 6,239,139 and U.S. Pat. No. 6,255,317 disclose berberine derivatives bearing alkyl, alkenyl, cycloalkylalkyl, haloalkyl, ethoxycarbonyl, ethoxycarbonylmethyl, hydroxycarbonylmethyl, ethoxycarbonylethyl, and 2-valerolactonyl groups in position 13, as inhibitors of cholesterol biosynthesis. There is no mention about an antitumour activity and/or additional (hetero)aromatic moieties linked to the substituents in position 13.
WO 2008/040192 discloses berberine derivatives bearing lower alkyl, lower alkoxy and acetic acid lower alkyl esters in position 13. The said derivatives are glucose sorbefacient to muscle cells and have medical effects for improving glucose-tolerance and insulin-resistance, and can be used for treating diabetes mellitus, adiposity, fatty liver and their complications caused by insulin resistance. There is no mention about an antitumour activity and/or additional (hetero)aromatic moieties linked to the substituents in position 13.
Eur. J. Med. Chem., 31, 469, 1996 reports berberine analogues substituted in position 13 by solely unsubstituted lower alkyl groups as antibacterial agents.
Life Sciences 73, 1401, 2003 describes the effects of 13-methyl and 13-ethyl berberine on the expression of certain proteins in connection with a reported antibacterial activity.
Bioorg. Med. Chem. Lett. 16, 1707, 2006, discloses the compound 13-(piperidinopropyl) berberine and its binding to natural and synthetic G-quadruplex DNA structures.
Bioorg. Med. Chem. Lett. 19, 954, 2009, discloses various 13-alkyl and 13-benzyl 5,6-dihydrodibenzo[a,g]quinolizinium compounds as P2X7 receptor antagonists as potential anti-inflammatory and immunomodulating agents.
J. Med. Chem, 52, 492, 2009 reports berberine analogues substituted in position 13 by solely lower alkyl and benzyl groups as LDL receptor up-regulators.